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Citation
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HERO ID
7109003
Reference Type
Journal Article
Title
Flufenamic acid as an inducer of mitochondrial permeability transition
Author(s)
Jordani, MC; Santos, AC; Prado, IMR; Uyemura, SA; Curti, C; ,
Year
2000
Is Peer Reviewed?
1
Journal
Molecular and Cellular Biochemistry
ISSN:
0300-8177
EISSN:
1573-4919
Publisher
KLUWER ACADEMIC PUBL
Location
DORDRECHT
Volume
210
Issue
1-2
Page Numbers
153-158
Language
English
PMID
10976768
DOI
10.1023/A:1007185825101
Web of Science Id
WOS:000088224500017
Abstract
To assess the mechanism by which mitochondrial permeability transition (MPT) is induced by the nonpolar carboxylic acids, we investigated the effects of flufenamic acid (3'-trifluoromethyl diphenylamine-2-carboxylic acid, FA) on mitochondrial respiration, electrical transmembrane potential difference (Delta Psi), osmotic swelling, Ca2+ efflux, NAD(P)H oxidation and reactive oxygen species (ROS) generation. Succinate-energized isolated rat liver mitochondria incubated in the absence or presence of 10 mu M Ca2+, 5 mu M ruthenium red (RR) or 1 mu M cyclosporin A (CsA) were used. The dose response-curves for both respiration release and Delta Psi dissipation were nearly linear, presenting an IC50 of approximately 10 mu M and reaching saturation within 25-50 mu M, indicating that FA causes mitochondrial uncoupling by a protonophoric mechanism. Within this same concentration range FA showed the ability to induce MPT in energized mitochondria incubated with 10 mu M Ca2+, followed by Delta Psi dissipation and Ca2+ efflux, and even in deenergized mitochondria incubated with 0.5 mM Ca2+. ADP, Mg2+, trifluoperazine (TFP) and N-ethylmaleimide (NEM) reduced the extent of FA-promoted swelling in energized mitochondria by approximately one half, whereas dithiothreitol (DTT) slightly enhanced it. NAD(P)H oxidation and ROS generation (H2O2 production) by mitochondria were markedly stimulated by FA; these responses were partly prevented by CsA, suggesting that they may be implicated as both a cause and effect of FA-induced MPT. FA incubated with mitochondria under swelling assay conditions caused a decrease of approximately 40% in the content of protein thiol groups reacting with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB). The present results are consistent with a ROS-intermediated sensitization of MPT by a direct or indirect FA interaction with inner mitochondrial membrane at a site which is in equilibrium with the NAD(P)H pool, namely thiol groups of integral membrane proteins.
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PFAS
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PFAS Universe
Data Source
Web of Science
Pubmed
3,3,3-Trifluoro-1-propene
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